One of the most significant events in the evolution of animal physiology was the internalization of the skeletal framework. In a broad sense, it allowed for substantial increases in size while retaining the mobility necessary to exploit new environments. Moreover, in higher organisms the skeletal system carries out several important functions. Fundamentally, it provides mechanical support for the tissues of the body and assists in the maintaining the body's natural mineral balance. It also exhibits a protective nature, reducing the potential for harm to delicate internal organs. Perhaps most importantly, the skeletal system is a dynamic structure incorporating numerous joints and providing a framework on which muscles can act to allow motion. Responsive to neural signals, this coordinated interaction is the basis for all voluntary movement.
The adult human skeleton is made up of 206 individual bones. The sites where the bones come together are commonly called joints (arthroses) or points of articulation. In normal operation, joints efficiently function to provide smooth, painless, stable, force transmission between one bone and the next with little effort. For the average adult individual, the joints cycle more than one million times a year, typically without injury or mishap. The hip, knee and ankle joints transmit forces of three times body weight with the simplest of activities such as walking, and over seven times the body weight when undergoing motion related to climbing stairs. Because much of the force transmitted across a joint is due to agonistic muscle contraction, the force per unit area carried by all extremity joints is similar.
Based on the nature of their connective tissue, joints are generally classified as belonging to one of two principal groups. In the first group, connective tissues remain solid (synarthroses). These solid joints are further classified as being fibrous joints or cartilaginous joints based on the most prevalent type of connective tissue. Fibrous joints tend to be articulations in which the surfaces of the bones are fastened together by intervening fibrous tissue. Such joints, including those between cranial bones, tend to allow little appreciable motion. Cartilaginous joints include synchondroses (primary cartilaginous joints) and symphyses (secondary cartilaginous joints) each of which may allow limited movement. The former are essentially growth mechanisms and are found where two separate but adjacent regions of ossification occur within a continuous mass of hyaline cartilage. In most cases, the cartilage is converted ultimately to bone and the synchondrosis is replaced by complete bony union, i.e. a synostosis. Symphyses, including the intervertebral discs, consist of two well-defined, hyaline cartilage-covered bones bonded by a strong, solid connective tissue such as fibrocartilage.
The second major group of joints, the predominant form of joint in the human body, are termed diarthroses or synovial joints. Synovial joints, which allow for a wide range of motion, incorporate a fluid filled cavity (the articular cavity) having a membrane known as the synovium. The synovium (or synovial membrane), richly supplied by both blood vessels and lymphatics, terminates at the margin of articular cartilage and is supported by the fibrous tissue defining the cavity or capsule. Only a few cell layers thick under normal circumstances, the synovium helps regulate the amount of liquid in a joint by secreting and absorbing synovial fluid. The synovial fluid plays an important role in lubricating and separating the bone and cartilaginous surfaces comprising the joint. More specifically, the bone surfaces are typically covered by articular cartilage, a specialized form of hyaline cartilage, which has a very low coefficient of friction. Sliding contact is facilitated by the presence of the synovial fluid, which, among other functions, provides for lubrication and maintenance of the living cells in the cartilage. Where the congruity between the bones is low there may also be an articular disc or meniscus of fibrocartilage. The purpose of this fibrocartilage is uncertain although it has been suggested that it plays a part in shock absorption, improvement of fit between surfaces and spreading of weight over a larger area. In any case, the synovial joints allow an impressive array of movements while successfully supporting immense loads.
The presence of healthy cartilaginous tissue is critical for the effective operation of synovial joints. Bathed by synovial fluid, cartilage provides a smooth, relatively malleable surface allowing for almost frictionless movement. Histologically, articular cartilage is avascular and lacking in nerve structures. It contains a relatively small number of cells (chondrocytes) in a stiff, gel-like extracellular matrix that is permeated by a network of collagen fibers. Synthesis, and to some extent degradation, of the cartilage matrix is undertaken by the chondrocytes. The unusual mechanical characteristics of cartilage are a result of the unique architectural combination as well as chemical interactions between the components. Mechanically, articular cartilage can be considered to be a fluid-filled, permeable, porous solid. It is efficient at resisting the large compressive forces generated by weight transmission during movement and its elasticity dissipates the effect of concussion. During normal joint operation, the cartilage is subjected to both mechanical distortion of the matrix and, as a result of movement of interstitial fluid in and out of the tissue, changes in volume. The movement of synovial fluid, both within the cartilage and in the articular cavity, is extremely important to proper joint function.
Synovial fluid is a dialysate of blood plasma into which hyaluronate, a glycosaminoglycan of high molecular weight is secreted by the synovial membrane. The high levels of hyaluronate dissolved in the synovial fluid tend to make it fairly viscous under normal physiological conditions. In humans, the volume of synovial fluid found in the joints is typically on the order of a few tenths of a milliliter to several milliliters which is deposited on, and permeates, the cartilage and other surfaces within the articular cavity. Besides providing the articular cartilage its smooth texture and appearance, synovial fluid is found in the bursa (small synovium lined cavities associated with ligaments) where it provides lubrication for the tendon sheaths. Collectively, the bursa and articular cavity are known as synovial cavities. The dispersion of the fluid on the critical parts of the joint plays a decisive role in transmuting the dry resistant surfaces into effective load bearing structures exhibiting very low friction. For instance, it has been reported that the friction between articular cartilage surfaces is one third that of ice on ice. Yet, the efficiency of the lubrication depends, at least in part, on the quality and smoothness of the cartilage. In joints exhibiting damaged or degenerate cartilage, surface irregularities impair the lubricating properties of the synovial fluid and increase the rate of wear. Accordingly, while the initial disruption of the cartilage may occur for any one of a number of reasons, destruction of the joint is often due to a reduction in lubrication efficiency and repetitive insult to the tissue.
Several mechanisms have been proposed to explain the degree of lubrication and/or cushioning provided by the synovial fluid. For example, fluid film lubrication, involving a relatively thick layer of liquid interposed between the surfaces, is generally accepted to play a role in joint function. Different forms of fluid film lubrication that act in synovial lubrication, depending on the loading of the joint, include hydrostatic, hydrodynamic, squeeze-film and elastohydrodynamic. It has also been proposed that, under certain conditions, boundary layer lubrication may occur. In this case, it is believed that a layer of water and glycoproteins adheres to each surface thus reducing the amount of direct contact. Moreover, solvent cohesion during boundary layer lubrication allows the synovial fluid to function as an adhesive, thereby promoting joint stability. Solvent cohesion is apparently the result of hydrogen bonding where the bonds have a relatively high tensile strength but little or no resistance to shear. Such a system enables opposing surfaces to slide freely across each other but limits their distraction.
Although normally functioning joints provide pain free, efficient movement, this is not generally the case when the joint has been damaged. Deterioration of joint function may lead to chronic pain, lack of mobility and, in extreme cases, total disability or even death. Unfortunately a multitude of diseases can affect the joints. Some may occur due to infection while others are the result of autoimmune disorders. In yet other cases, the joints may be functionally impaired or damaged by congenital disorders, age, trauma or repetitive mechanical stress over an extended period of time. Irrespective of the etiology, progressive and irreversible physiological degeneration often results. Quite often the synovial fluid in the joint (or joints) is lost or reduced in volume, thereby exacerbating the problem. Typically, degenerated cartilage is shed into the bursa or articular cavity where it is engulfed by the synovium. This leads to chronic reactive hyperemia in the synovial membrane with corresponding fibrosis and loss of elasticity in the subsynovial tissue. Gradually adhesions obliterate the synovial space and reduce or eliminate the synovial fluid. The loss of structural integrity leads to swelling, inflammation, and a reduction of joint mobility, a condition commonly known as rheumatism or arthritis.
In the past, rheumatism was the generic name for pain and stiffness associated with joints, muscles and related structures. Arthritis is more properly used where degeneration results in the inflammation of joints or connective tissue. However, the term is still often used generically to describe cases where inflammation does not occur. It is estimated that up to 33% of all adults are currently affected, at least temporarily, by some form of articular disorder. Of the more than 100 different types of articular disorder commonly termed "arthritis", the most common are osteoarthritis, rheumatoid arthritis, gout, pseudogout and ankylosing spondylitis. These five conditions account for more than half of all types of joint disease diagnosed today. Other less common, though still serious, types of arthritis include juvenile arthritis, lupus, scleroderma, chondromalacia patellae, and infectious arthritis. Still other types of articular disorders involve inflammation or irritation of the structures supporting the joint, such as muscles, tendons and ligaments. These condition include bursitis, tendinitis, fibrositis and polymyositis.
By far, the most prevalent articular disorders are rheumatoid arthritis and osteoarthritis which is also known as degenerative joint disease. Rheumatoid arthritis, thought to be an autoimmune disorder, is the result of an inflammation of the synovial membrane. Peak onset of the disorder occurs in the 30s and 40s and afflicts women three times more often than men. In extreme cases, chronic inflammation erodes and distorts the joint surfaces and connective tissue resulting in severe articular deformity and constant pain. Moreover, rheumatoid arthritis often leads to osteoarthritis, further compounding the destruction of the joint. The most common articular disorder, osteoarthritis is characterized by degenerative changes in the surface of the articular cartilage. Alterations in the physicochemical structure of the cartilage make it less resistant to compressive and tensile forces. Finally complete erosion occurs, leaving the subchondral bone exposed and susceptible to wear. Joints of the knees and hands are most often affected, followed by the spine, hips, ankles and shoulder. In both rheumatoid arthritis and osteoarthritis, degeneration of the weight bearing joints such as the hips and knees can be especially debilitating and often requires surgery to relieve pain and increase mobility.
No means currently exist for halting or reversing the degenerative changes brought about by these disorders. At the same time, approximately 37 million Americans seek symptomatic relief in the form of prescription drugs. In such cases nonsteroidal, anti-inflammatory drugs (NSAIDS) are most often prescribed. While these compounds often alleviate the arthritic symptoms, they are not without side effects such as nausea and gastrointestinal ulceration. Another class of commonly prescribed compounds are corticosteroid such as triamcinolone, prednisolone and hydrocortisone. Yet, the long term use of such measures increases the chance of undesirable side effects and is often contraindicated. In addition to difficulties in determining effective dosages, a number of adverse reactions have been reported during intra-articular steroid treatment. As a result, the use of corticosteroid treatments in the management of articular disorders is currently being reassessed.
Formulations of hyaluronic acid, including gels and slurries as described in U.S. Pat. No. 5,143,724, have also been proposed for use in the treatment of arthritis. However, the use of such treatments has been limited as hyaluronic acid is reported to lubricate only the soft tissues of the joint which are not subject to heavy loading. Further, as with more conventional treatments, adverse side effects have been observed following the intra-articular administration of the formulation. Significantly, patients with clinical histories of local adverse reactions to the hyaluronic acid treatment are reportedly susceptible to severe permanent joint damage. Accordingly, widespread use of the disclosed formulations has yet to be achieved.
In addition to the intra-articular injection of natural polymers such as hyaluronan, the administration of synthetic polymers has also been used for the management of articular disorders. For example, U.S. Pat. No. 4,828,828 discloses methods of treating degenerative joint disease through the intra-articular injection of meth(acrylamide) (co)-polymers in the form if a gel. However, acrylamide monomers are known to be potent neurotoxins making such gels undesirable for long term therapeutic administration. Questions involving breakdown products and bioincorporation of the constituent material complicate necessary regulatory approval. Similarly, U.S. Pat. No. 3,697,653 describes a method of treating osteoarthritic joints with polysiloxanes. While the disclosed materials possess some of the desired qualities for the proposed use, the presence of free silicone and silicone derivatives have recently been associated with immune disorders and connective tissue disease. In particular, silicone breast implants incorporating polysiloxanes have been implicated in the etiology of autoimmune disorders, immune suppression, connective tissue disease and, perhaps most importantly, rheumatoid arthritis. As such, it is possible that the intra-articular administration of siloxane polymers will exacerbate any preexisting arthritic condition.
Accordingly, it is an object of the present invention to provide methods for the treatment of articular disorders.
It is another object of the present invention to provide methods for the reduction of articular inflammation.
It is yet another object of the present invention to provide methods for the articular administration of therapeutic compounds.
It is still another object of the present invention to provide methods of imaging an articular region providing enhanced contrast.